Dr. Fujise's long-term objectives is to serve as a molecular biologist and cardiologist, whose main focus is prevention and treatment of cardiovascular diseases using molecular biological approach. Under the guidance and direction of Dr. Edward T.H. Yeh, Dr. Fujise has performed the research in the field of apoptosis regulation. In the process of characterizing MCL1(ML1 myeloid cell leukemia), a Bcl-2 homologue, Dr. Fujise discovered a novel interaction between MCL1 and PCNA (Proliferating cell nuclear antigen). PCNA is a 29kDa nuclear protein involved in DNA repair and replication and cell proliferation and differentiation. The role of PCNA has been implicated in pathogenesis of SLE (Systemic lupus erythematosis), restenosis after angioplasty and others. Apoptosis as well as the lack of it play critical roles in many human diseases including cancer, AIDS, myocarditis, atherosclerosis and myocardial infarction. The MCL1-PCNA interaction may be an important molecular link between anti-apoptotic proteins and cell cycle proteins. Based on the hypothesis that MCL1 plays a role in DNA repair and replication and cell proliferation and differentiation through its interaction with PCNA, Dr. Fujise here proposes to characterize the MCL1-PCNA interaction over the five years of the Award. First, Dr. Fujise will further characterize biochemical aspects of MCL1-PCNA interaction, using yeast two hybrid system. Second, Dr. Fujise will investigate the functional significance of the MCL1-PCNA interaction, including the effect of MCL1 over- expression on cell proliferation and the effect of MCL1 on DNA polymerase delta, DNA methylase, and DNA repair enzymes in the presence of PCNA. Finally, the impact of cell cycle phases, phosphorylation and DNA damage on MCL1-PCNA interaction and MCL1's subcellular localization will be evaluated. With Dr. Yeh as his Mentor, Dr. Fujise will perform his research at Research Center for Cardiovascular Diseases within the Institute of Molecular Medicine for Prevention of Human Diseases, devoting 80 percent of his professional time to the research. The Research Center and Institute will provide Dr. Fujise with a highly interactive and productive environment as well as with all the equipment needed for his research. The Scientific Advisory Committee, consisting of three senior scientists including the mentor will guide Dr. Fujise's scientific progress. At the completion of this Award, Dr. Fujise will be an independent, highly productive investigator with a high likelihood of making critical contributions in the fieled of apoptosis regulations and in prevention and treatment of cardiac diseases.